ABSTRACT Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by defective social interaction, impaired communication and restricted patterns of repetitive behaviors. In US, 1 in 88 children are diagnosed with autism, which presents an ever-growing challenge for the families, as well as education and healthcare systems. The etiology of ASD is elusive, combining genetic, epigenetic and environmental risks. To this date, the effective treatment for ASD is limited. To find innovative solutions, it is important to understand the cellular and molecular mechanisms underlying ASD. Although ASD involves many brain regions, emerging evidence suggests that aberrant activity of the cerebellum in the early developmental stage can lead to autism. The cerebellum integrates multiple sensory inputs and connect to diverse brain areas that are important for cognition and affection. Within the cerebellar circuitry, Purkinje neurons (PNs) receive excitatory and inhibitory synaptic inputs and generate the sole output. Although excitation provides the drive for PN firing, the firing rate and patterns are dictated by feedforward inhibition from GABAergic interneurons (INs). To elucidate the non- conventional role of the cerebellum in ASD, we have employed two widely accepted mouse models for ASD: one mimics the most common genetic form of ASD, Fragile X syndrome; and the other is a spontaneous mutation with face validity to ASD. In both cases, we have revealed a significant reduction in the PN activity due to over- inhibition from upstream INs. In Aim 1, we identify heterogeneous molecular underpinnings of the abnormal neuronal excitability in the inhibitory pathway. Namely, downregulation of Kv1.2 potassium channels increases the excitability of INs, resulting in the presynaptic over-inhibition. Decreased expression of hyperpolarization- activated cyclic nucleotide-gated (HCN) channels lowers the intrinsic excitability of PNs, further impairing the output activity from the cerebellar cortex. By revealing the new molecular targets, we develop pharmacological reagents with low toxicity to rectify the cellular, circuitry and behavioral phenotypes of the ASD models. In Aim 2, we design novel chemogenetic approaches to selectively manipulate the excitability of INs and PNs to elucidate the necessity and sufficiency of the cerebellar circuits in mediating the pathogenesis of ASD and instigate genetic rescues for the mouse ASD-like behaviors. In addition to setting foundation for clinical intervention of ASD, this project will transform the research landscape in our regional institute and anchors an exceptional training platform for next generations of neuroscientists.